Crosslinked silane coating for medical devices

ABSTRACT

Coatings are provided in which surfaces may be activated by covalently bonding a combination ofsilane derivatives (A) to the metal surface, covalently bonding a lactone polymer (B) to the silane derivative by in situ ring opening polymerization, and depositing at least one layer of a polyester (C) on the bonded lactone polymer. Biologically active agents or therapeutic compounds may be deposited with any of the polyester layers. Such coated surfaces may be useful in medical devices, in particular stents.

FIELD OF THE INVENTION

This invention generally relates to at least one polymer layercovalently bonded to an activated surface. More particularly, a layer ofpolymer coating contains at least one biologically active agent that isapplied to the surface of a medical device such as a stent. Theinvention further relates to methods of coating metals surfaces andpreparing medical devices.

BACKGROUND OF THE INVENTION

Medical devices are commonly implanted into the body to treat variousconditions. These medical devices are commonly constructed from polymersor metal, for example, a polymeric or metallic stent utilized to treatrestenosis within a conduit of a body such as a blood vessel or biliaryduct. The placement of metal or polymeric devices in the body can giverise to numerous complications. Some of these complications includeincreased risk of infection, initiation of a foreign body responseresulting in inflammation and fibrous encapsulation, and/or initiationof a wound healing response resulting in hyperplasia and/or restenosis.These and other possible complications must be dealt with whenintroducing a metal or polymeric device into the body.

One approach to reducing the potential harmful effects is to improve thebiocompatibility of the device. While there are several methodsavailable to improve the biocompatibility of devices, one method thathas met with limited success is to provide the device with the abilityto deliver therapeutic and/or other biologically active agents to thevicinity of the implant. By so doing, some of the harmful effectsassociated with the implantation of medical devices are diminished. Forexample, antibiotics can be released from the device to minimize thepossibility of infection, and anti-proliferative drugs can be releasedto inhibit hyperplasia. Another benefit is to localize the release ofthe therapeutic and/or biologically active agent(s) to the area wherethey are most needed. This avoids the spread of therapeutic and/orbiologically active agent(s) to areas where they may prove toxic. It isalso desired that therapeutic agents be released for long periods oftime (days, weeks, or months) instead of an instantaneous release uponimplant of the device.

Typically, a therapeutic agent is applied to the surface of a device viaa polymer matrix. For example, in the case of a metallic device, a metaloxide is created to activate the surface. Thereafter a layer is formedon the activated metal surface that serves as a platform for a primerlayer. A polymer blended with a biologically active agent or therapeuticagent that readily adheres to the primer layer may be employed. In manyrespects, the success of the polymer coatings depends on the nature ofthe contact between at least the polymer layer adjacent to the metalsurface and the underlying metal surface. In particular, if the polymercracks or peels away from the metal surface, the polymer layer havingthe biologically active agent will fail to perform.

Providing a device with a polymer containing a biologically active agentpresents several challenges. When a polymer layer contains abiologically active agent the resulting polymer/biologically activeagent composite may be prone to dilation, swelling, degradation, and/orvolume changes because of interactions of the incorporated compound withaqueous environments of the body. Also, following the penetration ofwater into the polymer layer, dissolution of the compound and itssubsequent release, may change the structure and porosity of thecomposite. In addition, due to penetration of water following drugdissolution, the polymer layer could be exposed to a mechanical stressdue to osmotic forces. These effects may result in detachment of thepolymer layer and its peeling from the metal surface.

U.S. Pat. No. 6,013,855—McPherson, describes methods for graftinghydrophilic polymers onto metal surfaces. This method included exposingthe device surface to a silane coupling agent and causing the agent tobe covalently bound to the hydrophilic device surface. The bonded silanelayer was then exposed to a polymer such that the hydrophilic polymerbecame covalently bound to the silane layer. Of course, a deviceproduced using this method will produce a primer layer that is unable tobe derivatized and will remain on the device. In addition, the use of ahydrophilic polymer will expose the interface of the surface of thedevice and the polymer to osmotic forces that may cause separation.

The selection of the polymeric materials employed to coat the medicaldevice is also an important consideration. There are only a small numberof polymers possessing the physical characteristics that would renderthem useful for implantable medical devices since most devices undergoflexion and/or expansion during and upon implantation. Many polymersthat demonstrate good drug release characteristics, when used alone asdrug delivery vehicles, provide coatings that are too brittle to be usedon devices that undergo flexion and/or expansion.

As stated above, biologically active and/or therapeutic agents areapplied to medical devices to increase biocompatibility. Thus, inaddition to creating a stable interface between the device and thepolymer layer containing the biologically active agent, it is alsodesired to ensure any polymeric materials that may have an adverseaffect on the body are removed. For example, after the therapeutic agentis released, several polymer layers or layers of other materials,including the primer layer will remain on the surface of the device.This can lead to undesirable complications such as restenosis and/orthrombosis. Other polymers can create an inflammatory response whenimplanted.

Insung S. Choi and Robert Langer, in “Surface-Initiated polymerizationof l-Lactide: coating of solid substrates with a biodegradable polymer”,Macromolecules (2001) 34, 5361-5363, discloses an in-situ polymerizationof lactone polymers with stannous octoate (Sn(Oc)₂) as a catalyst on asolid surface such as metal modified with a hydroxyl or amine terminatedsilane derivative. International Publication No. WO20030068289—Rypaceket al, uses essentially the same strategy as in the Choi article to makea device having a silane layer which is modified to polymerize acomposition such that a lactone polymer layer on the silane layer. Thislayer is bioabsorbable and provides a surface on which additionalbioabsorbable polymer layers may be applied. Thus, these layers areremoved after delivery of the therapeutic agent is complete. In creatingthe lactone polymer layer, however, a heavy metal based catalyst, suchas stannous octoate, is employed and remains inside the coating.Certainly, biocompatibility is not optimized with heavy metals presentin a patient's body. Moreover, the lactone polymer layer lacks adequatedensity. Thus, any additional polmer layer, for example, a polymercontaining a biologically active agent and/or therapeutic agent, appliedto the lactone polymer layer will not adhere optimally. This may causeseparation of the layers causing a failure to deliver the biologicallyactive and/or therapeutic agent.

It is desired to provide a coating for a medical device that isbioabsorbable and will provide a dense and stable platform onto whichadditional bioabsorbable layers may be applied.

SUMMARY OF THE INVENTION

The invention provides for a surface treatment and method for applying asurface treatment to a surface with an activating layer of crosslinkedsilane derivatives bound to the surface. The surface-activating layer isa siloxane polymer having one or both of sulfhydryl or epoxide terminalgroups on the siloxane. A first layer of one or more lactone polymers iscovalently bonded to the polymerized silane derivative. Additionalpolymer layers may be applied to the first layer. In one embodiment ofthe invention, the composition of the first layer or the additionallayer(s), or both, includes one or more biologically active agents. Thebiologically active agent(s) is about 0.5 to about 60 percent by weightof the first or additional layer(s). The biologically active agent ortherapeutic compound is released from the composition in an aqueousenvironment.

The first layer and the additional layer(s) have at least one layer ofone or more lactone polymers. In the first layer, the lactone polymermay be a lactone homopolymer such as polyglycolide, poly(L-lactide),poly(D-lactide), poly(-caprolactone), poly(p-dioxanone),poly(dioxepanone), or a lactone copolymer such aspoly(L-lactide-co-D-Lactide), poly(L-lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(lactide-co-caprolactone), poly(lactide-co-dioxanone),poly(D,L-lactide), or poly(lactide-co-dioxepanone).

In the additional layer(s), the polyester polymer may be either alactone homopolymer, a random copolymer, or a block copolymer with atleast one polylactone block, while the other block or blocks of thecopolymer may be a polyether, a poly(amino acid), a poly(acrylate), or apoly(methacrylate). In a preferred embodiment of the invention, thepolymer of the additional layer(s) has a molecular weight of 10³ to 10⁶.

In various preferred embodiments, the first layer is a polylactide andthe additional layer is one or more polymers such as poly(l-lactide),poly(glycolide), poly(lactide-co-glycolide) or poly(d,l-lactide), andthe mole fraction of L-lactide structural units is in the range ofeither 0.5 to 1.0 or 0 to 0.5. The biologically active agent is about0.5 to 60 percent of the total mass of polymer of the additionallayer(s).

In another preferred embodiment of the invention, the composition of theinner additional sublayer is a semicrystalline polymer, or an amourphouspolymer, or a semicrystalline mixture of polymers, and the outeradditional sublayer comprises at least one amorphous polymer. Thepolymer of an inner additional sublayer may be a hydrophobic polymerwhich is either a lactone homopolymer, a statistical lactone copolymer,a lactone block copolymer, and the polymer of an outer additionalsublayer is an amphiphilic copolymer of at least one of a statisticalcopolymer and a block copolymer of lactones and ethylene oxide.

Yet another embodiment of the invention includes a method of coating asurface such as a metal, ceramic or glass surface. The method includesreacting the surface with a silane-based activating agent to form asurface having an activated layer with at least two functionalterminals, one of which functions as a non-metallic in situ catalyst,for example one not containing tin. At least one lactone monomer ordimer is polymerized employing ring opening polymerization to form thefirst polymer layer on the surface. Additional layer(s) may be depositedonto the first polymer layer, for example, by applying at least onesolvent solution comprising a polymer on the first layer and evaporatingthe solvent to form at least one additional layer adhered to the firstlayer.

The preferred silane-based activating agent is a silane derivative ofgeneral formula:(RO)₃Si(CH₂)_(n)XRO is a hydrolysable group, such as methoxy, ethoxy, or acetoxy, and Xis an organofuntional group, such as amino, methacryloxy, epoxy, etc. Rcan be independently selected from substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted aralkyl, substitutedheteroaryl, and substituted alkoxy, with the proviso that R ispreferably the same for all 3 R groups. N is an integer ranging from 1to 10. Other similar space between the silicon atom and theorganofucntional group X can contain additional structural element suchas ether, ester, etc. provided that they do not interfere with thesilylating process or the subsequence reactions.

A silane-coupling agent acts as an interface between an inorganicsubstrate (such as glass, metal or mineral and an organic material (suchas an organic polymer, coating or adhesive) to bond, or couple, the twodissimilar materials. Silane coupling agents that contain threeinorganic reactive groups on the silicon (usually methoxy, ethoxy oracetoxy) will bond well to the metal hydroxyl groups on most inorganicsubstrates, especially if the substrate contains silicon, aluminum or aheavy metal in its structure. The alkoxy groups on silicon hydrolyze tosilanols, either through the addition of water or from residual water onthe inorganic surface. The silanols coordinate with metal hydroxylgroups on the inorganic surface to form an oxane bond and eliminatewater.

In yet another embodiment the silane-based activating agent is appliedin a solution or in a vapor phase to form an activating layer bound tothe surface. The oxidation of the sulfhydryl group to sulfonic acidgroup can be achieved by adding a solution containing hydrogen peroxidein methanol to the activated surface. The derivatization of the epoxygroup is achieved by adding a bifunctional agent such as a diamine or adiol to the solution containing the activated surface with epoxyterminal groups. The original epoxy group will be transformed to abifunctional group of a diol if a diol is used for the conversion, or abifunctional group comprising a hydroxyl and an amine group if a diamineis used for the conversion. This transformation serves to double thedensity of the functional groups on the surface. The final silanizedsurface can be then rinsed with a common organic solvent such astetrahydrofuran to remove excess reagents before the first polymerconjugation process.

Both the hydroxyl and amine group serves as the initial point for thering opening polymerization with the nearby sulfonic acid serving as ametal free in situ catalyst of the ring opening polymerization.Formation of a first layer by lactone rign opening polymerizationincludes immersing an activated surface with both sulfonic acid groupand multiple hydroxyl and amine groups in a lactone dimer or monomersolution, or a lactone dimer or monomer melt at a temperature sufficientto keep the lactone in the molten state for a time sufficient to allowthe in-situ ring opening polymerization of the lactone on the activatedsurfade to form the first lactone polymer layer.

Formation of an additional layer includes the deposition of a solventsolution containing the polymer onto the first layer by bringing a metalsurface having the activation layer and first layer into contact with apolymer solution by dipping the surface into the solvent solution orspraying, casting, pouring or spreading the solution onto the surface,and evaporating the excess solvent. The solvent solution may contain oneor more biologically active or therapeutic compounds. In certainembodiments, the solvent is an aprotic solvent such as an ether, ketone;aromatic hydrocarbon and a mixture of these solvents.

In yet another embodiment, the invention provides for a medical devicehaving a metal surface with a metal-activating layer of polymerizedsilane derivatives covalently bonded to the metal surface, a first layerof a polylactone covalently bonded to the polymerized silanederivatives, and a additional layer of a polymer adhered to the firstlayer, where the additional layer has a biologically active agent(s)and/or therapeutic agents releaseably associated with the polymer. Thebiologically active agent(s) and/or therapeutic agents may be about 0.5to 60% by weight of the additional layer. The medical device maycomprise, for example, a stent, vascular graft tubing, a bloodoxygenator, an intravascular balloon, a catheter, an implantable pulsegenerator, an electrode, an electrical lead, sutures, a soft or hardtissue prosthesis, or an artificial organ.

DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic representation of a surface coated in accordancewith the present invention.

FIG. 2 is a schematic representation of the hydrolysis of alkoxysilanein the activation process.

FIG. 3 is a schematic representation of bonding of silane agent to aninorganic substrate.

FIG. 4 is a schematic representation of bonding of silane agentcontaining a sulfhydryl group and an epoxy group to a surface.

FIG. 5 is a reaction scheme of the conversion of a sulfhydryl group to asulfonic acid and an epoxide group to multi-functional terminals.

FIG. 6 is a schematic representation of the reaction mechanism andstructure involved in ring opening polymerization of a lactone dimer ormonomer on the activated silane terminals.

DETAILED DESCRIPTION OF THE INVENTION

Polymer coating can improve the performance of a medical device byproviding a biocompatible interface between the metal surface and thesurrounding tissue, while the biological response of the organism,namely the local response of the surrounding tissue, can be modulated bysustained release of a suitable biologically active agent(s). A thinpolymer layer, that does not significantly affect mechanical propertiesof the device and that provides for a long-lasting matrix reservoir fora biologically active agent(s) to be released in a controlled manner,can be produced by a successive deposition of chemically compatiblepolymers on the metal surface of the implantable device.

An activating silane derivative interfacing the metal surface is boundto the metal surface to activate the surface and provide for suitablefunctional groups. Second, a polymer (first) layer is bound, for examplecovalently, to the activating layer. The covalent bond of the firstpolymer layer provides for adhesion of any subsequent polymer layers tothe surface of the device. This allows for a thin, durable andcontiguous film having an adjustable and repeatable release performance.This method is applicable for use with biocompatible, medicallyapplicable polymers, thus making the method suitable for coating medicaldevices.

As used herein, the terms listed below have the following definitions:

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “homopolymer” means a polymer derived from one species ofmonomer.

The term “copolymer” means a polymer derived from more than one speciesof monomer.

The term “random copolymer” means a copolymer consisting ofmacromolecules in which the sequential distribution of the monomericunits obeys known statistical laws, e.g. the sequential distribution ofmonomer units follows Markovian statistics.

The term “block copolymer” means a polymer composed of macromoleculesconsisting of a linear sequence of blocks, wherein the term “block”means a portion of macromolecule comprising many constitutional unitsthat has at least one feature that is not present in the adjacentportions.

The term “polymer matrix” refers to all of the polymer layers orsublayers on the metal surface. This can include activating, first,additional, and/or barrier layers.

The term “amphiphilic copolymer” means a polymer containing bothhydrophilic (water-soluble) and hydrophobic (water-insoluble) segments.

The term “polyester” means a polymer with structural units connected byester bonds, comprising polyesters obtained from dicarboxylic acids anddials, or from hydroxyalkanoic acids by polycondensation, and includespolylactones obtained by ring-opening polymerization of lactones, suchas polyglycolides polylactides, polycaprolactone and related copolymers.

The term “metal” means surfaces made of, for example, stainless steel,titanium or tantalum with oxide groups on their surface, as well asother surfaces made of, for example, polymers or glass, with hydroxylgroups or other functional groups that can be transformed to hydroxylgroups on their surfaces. The surface may be of any shape and may be apart of any medical devices. Examples of such devices include bothimplantable or extracorporeal devices such as vascular graft tubing,blood oxygenators, intravascular balloons, catheters, implantable pulsegenerators, electrodes, electrical leads, stems, sutures, soft or hardtissue prosthesis, artificial organs and the like. Further, there arelikely to be many applications for the coated metal outside the medicalfield. Accordingly, it will be appreciated by those skilled in the artthat the invention described may be applied to many medical devices andin fields outside of medicine where a polymer coated metal surface ofthe invention may be useful.

The words “flexion” and “expansion” as used herein with regard toimplantable devices will refer to a device, or portion thereof, that isbent and/or expanded either in the course of its placement, orthereafter in the course of its uses in vivo

Stents are designed to mechanically prevent the collapse and reocclusionof the coronary arteries. The coating composition can also be used tocoat stems, which are typically prepared from materials such asstainless steel, cobalt comium or tantalum or from a polymer, polymerblend, or a polymer/polymer blend having additives and agents. A varietyof stent configurations are known including but not limited to shapememory alloy stems, expandable stents and stents formed in situ e.g.,either self-expanding stents (such as the Wallstent variety), orballoon-expandable stents (as are available in a variety of styles, forinstance, Gianturco-Roubin, Palmaz-Shatz, Wiktor, Strecker, ACSMulti-Link, Cordis, AVE Micro Stent). Other suitable metals for suchstents include gold, molybdenum-rhenulm alloy, platinum-iridium alloyand combinations thereof. See, for example, U.S. Pat. Nos. 4,733,655,4,800,882 and 4,886,062, all of which are incorporated by reference intheir entirety.

The polymer coating or coating composition is applied to a surface 1 andcan be composed of several layers. Referring now to FIG. 1, the surfacehas a first coat 10, referred to herein as the activating layer that iscomposed of silane derivatives bound to the surface 10. If surface 10 ismetallic, it is first oxidized. A second layer 20, which may be a firstpolymer layer, is composed of a polylactone covalently bonded to themulti-functional terminals of the silane derivatives in layer 10.Additional layer(s) 30 may be deposited on layer 20. The additionallayer(s) 30 may optionally be composed of one or more sublayers of thesame or different polymers.

Layer 20 and the additional layer(s) 30 may optionally contain one ormore biologically active and/or therapeutic compounds, for example, adrug that is releasably dispersed in the matrix of a polymer coatingcomprising layer 30. Once the coated surface 1 is placed in an aqueousenvironment, typically body fluids, such as blood, lymph orextracellular fluids, the agent or biologically active compounds arereleased into the surrounding tissue or environment. The composition ofthe layer 20 and the additional layer(s) 30 may, for example, beadjusted to provide for a controlled release of these compounds into asurrounding aqueous medium and/or to modify the tissue reaction to thepresence of the device, for example, to make the surfacethromboresistant. The coated surface 1 may be composed of two or more;sublayers with different functions, optionally a top layer 40 mayfunction as a barrier or skin layer.

The biologically active and/or therapeutic agents useful in the presentinvention include virtually any substance that possesses desirablecharacteristics for application to the implant site. As used herein“biologically active agent and/or therapeutic agent” refers to a singleagent or multiple agents. For example, it is contemplated that one ormore biologically active and/or therapeutic agents may be releasablyassociated with the polymers on the metal surface. These agents include,but are not limited to: thrombin inhibitors, antithrombogenic agents,thrombolytic agents (e.g. factor Xa inhibitors), fibrinolytic agents,vasospasm inhibitors, calcium channel blockers, vasodilators,antihypertensive agents, antimicrombial agents, antibiotics, inhibitorsof surface glycoprotein receptors, antiplatelet agents, antimitotics,microtubule inhibitors, anti secretory agents, actin inhibitors,remodeling inhibitors, antisense nucleotide, anti metabolites,antiproliferatives (e.g. E2F antisense compounds, Rapamycin (sirolimus),tacrolimus, Taxol, paclitaxol, Cyclin Dependent Kinase inhibitors)anticancer chemotherapeutic agents, anti-inflammatory steroid ornon-steroidal anti-inflammatory agents, immunosuppressive agents, growthhormone antagonists (e.g. PDGF receptor tyrosine kinase inhibitors),growth factors, dopamine agonists, radiotheraputic agents, peptides,proteins, enzymes, extracellular matrix components, ACE inhibitors, freeradical scavengers, chelators, antioxidants, antipolyermases, ribozymes,antiviral agents, photodynamic therapy agents, and gene therapy agentssuch as 6-ylamino]-methyl}-benzoic acid.

The invention provides for the formation of the first layer covalentlybonded, grafted, or attached, to the surface-activating layer. Apretreatment of a surface, such as a metal surface, by an oxidizingagent prior to application of functional silane derivatives, forexample, the treatment of the metal surface by an oxidizing agent or acommercially available cleaning agent such as ENPREP can be used as apart or whole of the cleansing procedure.

The grafted first polymer layer is formed by the in-situ ring openingpolymerization of lactone monomers initiated by suitable functionalgroups of the silane derivatives on the activating layer and catalyzedby the sulfonic acid tethered to the silane derivatives. Suitablefunctional groups for initiating the grafting polymerization of lactones(“initiating functional groups”) can be created on surfaces through thereaction of a surface, for example a metallic surface, with selectedsiliane derivatives, referred to herein as functional silanederivatives. Typical functional silane derivatives can be found in “Aguide to silane selection” published by Dow Corning (reference 1). Othersuitable functional silane derivatives can be found in GELEST Catalogue2000: Silanes, Silicones and Metal-Organics. Gelest, Inc., Dr. BarryArkles, Tullytown, Pa., USA. I

To treat metal surfaces, a functional silane derivative can be appliedin solution or in a vapor phase. A variety of solvents and solventcompositions can be used. In this respect, numerous references areavailable, teaching the use of silane derivatives in sol-gel processesand as adhesion promoters in corrosion protection. For a review of thisart see for example, ller, R. K. The Chemistry of Silica, Wiley, NewYork, 1979; Brinker, J., Scherer, G. W., Sol-Gel Science: the Physicsand Chemistry of Sol-Gel Processing, Academic Press, New York, 1990;Jang, J., Kim, E. K. Corrosion Protection of Epoxy-Coated Steel UsingDifferent Silane Coupling Agents, J. Applied I Polym. Sci. (1999),71:585; Insung S. Choi and Robert Langer, Surface-Initiatedpolymerization of l-Lactide: coating of solid substrates with abiodegradable polymer, Macromolecules (2001) 34, 5361-5363; Benn C.Wilson and Christopher W. Jones, A Recoverabl, Metal-Free Catalysts forthe Green Polymerization of ipsilon-caprolactone, Macromolecules, (2004)37, 9709-9714; RYPÁCEK; Frantisek et. al, Polymer coating for medicaldevices, WO2003068289A1, Each of these references are incorporatedherein by reference in its entirety.

Following the silylation of the surface, a first lactone polymer layeris conjugated to the activated surface. To apply the polymer of thefirst layer, a first or grafting reaction is carried out by exposing thefunctional silane derivative-activated surface to a solution of lactonein a suitable aprotic solvent, or to a lactone in bulk. In theinitiation reaction of the grafting polymerization, the first lactonedimer or monomer forms a covalent bond with the multiple functionalterminals of the functional silane derivatives bound to the metalsurface.

In subsequent steps, the polylactone chain propagates by a stepwiseaddition of lactone dimer or monomer. The growing polymer chains thusremain covalently bound to the surface through its initial structuralunits. The chemical mechanisms that apply in the polymerization graftingused in this embodiment are analogous to those that apply in thering-opening polymerization of lactones in bulk or a solution. The fieldof lactone polymerization either in bulk or a solution is well describedin numerous literature and the principles of these reactions are knownto those skilled in the art.

Examples of the most frequently used polymerization reactions can befound in Dubois, P. et al., Aluminium Alkoxides: A Family of VersatileInitiators for the Ring-Opening Polymerization of Lactones and Lactides,Makromol. Chem., Macromol. Symp. (1991) 42/43:103-116; Inoue, S.,Coordination Ring-Opening Polymerization. Prog. Polymer. Sci. (1988)13:63-81; Jonte, J. M. et al., Polylactones.4. Cationic Polymerizationof Lactones by Means of Alkylsulfonates. J. Macromol. Sci.-Chem. (1986)A23:495-514; Kricheldorf, H. R. et al., Anionic and PseudoanionicPolymerization of Lactones-a Comparison. Makromol. Chem., Macromol.Symp. (1990), 32:285-298; Kricheldorf, H. R. et al., Poly(Lactones). 9.Polymerization Mechanism of Metal Alkoxide Initiated Polymerizations ofLactide Various Lactones, Macromolecules (1988) 21:286-293; and Lofgren,A. et al., J. M. S.-Rev. Macromol. Chem. Phys. (1995) C35:379-418,Insung S. Choi and Robert Langer, Surface-Initiated polymerization of1-Lactide: coating of solid substrates with a biodegradable polymer,Macromolecules (2001) 34, 5361-5363; Benn C. Wilson and Christopher W.Jones, A Recoverabl, Metal-Free Catalysts for the Green Polymerizationof ipsilon-caprolactone, Macromolecules, (2004) 37, 9709-9714; RYPÁCEK;Frantisek et. al, Polymer coating for medical devices, WO2003068289A1,each of which are incorporated by reference in their entirely

Suitable monomers and dimers in grafting ring polymerization of thefirst polymer layer are lactones. Typical examples of lactones includefour to seven-membered lactones, for example, the families of compoundscomprising oxetan-2-one and 4-alkyl-oxetan-2-one, dihydrofuran-2-one and5-alkyl-dihydrofuran-2-one, tetrahydropyran-2-one and6-alkyl-tetrahydropyran-2-one, oxepan-2-one and 7-alkyl-oxepan-2-one,1,4-dioxan-2,5-dione, 3,6-alkyl-1,4-dioxan-2,5-dione,1,3-dioxopan-2-one, 1,3-dioxan-2-one, 1,3-dioxolan-2-one,1,5-dioxepan-2-one, 1,4-dioxepan-2-one, 1,3-dioxepan-4-one, and theirsubstituted analogues, wherein the alkyl is C1-C10 alkyl or asubstituted alkyl.

In one embodiment of the invention the lactone monomer comprises lactide(3,6-dimethyl-1,4-dioxane-2,5-dione) in its various enantiomeric forms(L-lactide, D-lactide, meso-lactide and their mixtures), glycolide(1,4-dioxane-2,5-dione), and c-caprolactone. For the first layer,combinations of lactone monomers may be used to provide for graftingcopolymerization. These copolymers can be made available with differentratios of the co-monomers. Both the homopolymers and copolymers can beused in different molecular-weight ranges. Preferably, the lactonecopolymer includes one of poly(L-lactide-co-D-Lactide),poly(L-lactide-co-glycolide), poly(D-lactide-co glycolide),poly(D,L-lactide-co-glycolide), poly(lactide-co-caprolactone),poly(lactide-co dioxanone), and poly(lactide-co-dioxepanone).

Typical examples of aprotic solvents for carrying out the graftingreaction in solution include ethers (e.g., tetrahydrofuran, dioxane,di(ethylene glycol), diethyl ether), ketones (e.g. ethylmethyl ketone,diisobutyl ketone) and aromatic hydrocarbons (e.g. toluene, xylene), andmixtures of these solvents. Those skilled in the art can readilyidentify other solvents that would be useful for the grafting reaction.

The grafting ring polymerization at the functional terminals of thesilane derivatives can be carried out in the absence of solvent, i.e.,in the mixture formed by a lactone in bulk. In this mode of theinvention, the temperature of the reaction is preferably such as to keepthe lactone in a liquid state, such as above the melting temperature ofthe lactone. The reaction in lactone melt is carried out for the timenecessary to form a first layer of a desired thickness. After carryingout the reaction for a given time, the surface is removed from the melt,the residual lactone is washed from the surface by a suitable solventand the grafted surface is dried.

The covalently grafted polymer first layer is firmly bonded to thesurface. As a result, this first covalent bonded polymer layer isresistant to removal by treatment with solvents. Thermodynamicallysolvents, however, can penetrate into the grafted polymer layer, causingthe polymer chains to expand and thus become capable of adsorbing oraccumulating compounds from solutions. The adsorbed or accumulatedcompounds can be either biologically active agents or molecules ofanother polymer that have a similar or a compatible chemical structureor that are miscible with the grafted polymer. These features of thegrafted polylactone layer can be employed either for directincorporation of biologically active agents to be released from thelayer or for the design and attachment of other subsequent, welladherent, high-capacity polymer layers incorporating the agents.

When the polylactone first layer, grafted to the surface 1, is soaked ina solution of the biologically active agent in a solvent appropriate fora given polylactone, the solvent swells the first polymer layer makingit possible for the biologically active agent to penetrate the firstpolymer layer. After the solvent is stripped off by evaporation, whichcan be either spontaneous or assisted by the application of vacuum, thebiologically active agent, being less volatile than the solvent, isembedded in the polymer, the chains of which have condensed, thusbecoming closely packed into a compact matrix upon removal of solvent.Later, when the surface is put into an environment that is not a goodsolvent for the polymer, such as the aqueous environment of tissuefluids, the condensed polymer chains prevent the molecules of the agentfrom being rapidly dissolved or diffused into the aqueous medium. Thisaction extends the time period within which the agent is released.

According to another embodiment of the invention, the polylactone firstlayer grafted to the surface is soaked in a solution formed by a solventfor polylactone, a biologically active agent, and a polymer that ischemically compatible or miscible with the first layer. The polymerdeposited from the solution on the top of the grafted first layer formsthe additional layer on the surface. When the surface is soaked in thesolution, the solvent swells the grafted polymer first layer and thepolymer molecules that are to form the additional layer penetrate theswollen grafted first layer and entangle with the grafted chains.Additionally, the biologically active agent in solution may becomeembedded in the first layer.

In practice, the solution containing the polymer of the additional layeris applied to form a liquid film on the top of the grafted first layersurface. After the solvent has been evaporated from the solution, thesolidified polymer film of the additional layer will become well joinedwith the underlying grafted first layer due to mutual entanglements ofpolymer chains. Layers of polymers of various controllable thickness andcomposition can be applied to the anchoring grafted first layer to formsublayers of the additional layer. Biologically active agents containedin the solution with the polymer remain embedded in the solidifiedpolymer additional layer film. It is also possible to soak thepolylactone first layer grafted to the metal surface in a solution of abiologically active agent, using a good solvent for both the graftedpolylactone and the biologically active agent. The biologically activeagent will penetrate into the grafted polymer first layer that is beingswollen by the solvent and, after evaporation of the solvent, thebiologically active agent will then remain embedded in the graftedpolymer first layer.

Biologically active agents can be released from the solidified film ofbinder and/or additional layer into the aqueous environment by theirgradual dissolution and diffusion through the polymer matrix. Thisrelease may also be accomplished by polymer degradation alone, or inaddition to the diffusion of the biologically active agent through thepolymer matrix. By controlling the thickness and composition of thepolymer layers (e.g., first and additional), the capacity of the systemfor the loaded biologically active agent and the rate of its release canbe controlled. Accordingly, the biologically active agent is releasablyassociated with the polymer. When the coated metal surface is used as animplantable medical device, the biologically active agent can be locallyreleased from the polymer matrix in a controlled manner into a patientreceiving the medical device.

As described above, a stable and well adherent polymer matrix can beachieved through various combinations of the compositions of theadditional layer and the first layer using a variety of lactone polymersand copolymers by taking into account the chemical compatibility ormiscibility of the polymers of both layers. In various embodiments ofthe invention, the physical properties of the polymer coating matrix canbe modified while maintaining the compatibility of the first layer andthe additional layer. The composition of the polymers in the layers canbe adjusted by using either a chemical modification, such as statisticaland block copolymers, or a physical modification, such as blends orcomposites.

The polymers used for formation of the additional layer include lactonehomopolymers, examples of which include poly(L-lactide),poly(D-lactide), polyglycolide, poly(-caprolactone), poly(p-dioxanone,poly(dioxepanone), poly(trimethylene carbonate) statistical copolymersof lactones, examples of which may include poly(L-lactide-co-D-Lactide),poly(lactide-co-glycolide), poly(D,L-lactide),poly(lactide-co-caprolactone), poly(lactide-co-trimethylene carbonate)and other combinations of lactones that can be typically derived fromlactone monomers. These copolymers can be made with different ratios ofthe co-monomers. Both the homopolymers and copolymers can be used indifferent molecular-weight ranges.

The additional layer can also include a block copolymer containing atleast one polylactone block. The other blocks of the copolymer can bebased on polylactone or another chemical structure such as polyether,poly(amino acid), poly(acrylate), poly(methacrylate), polybutadiene,polyisoprene, etc. Typical examples of compositions of suitable blockcopolymers comprise polylactide/polycaprolactone,polylactide/poly(ethylene oxide), polycaprolactone/polybutadiene,polycaprolactone/poly(ethylene oxide), polylactide/poly(amino acid). Theblock copolymers can exhibit different ratios of block lengths,different numbers of blocks, and different molecular weights.

It is anticipated that the properties of copolymers may vary withdifferent ratios of co-monomers in the copolymers as well as they mayvary with molecular weight. The invention is not limited to anyparticular copolymer composition or a molecular weight range. Inaddition to changing the chemical constitution of the polymer molecules,the properties of polymer films formed can be modified also by blendingdifferent types of polymers, i.e. homopolymers, statistical and blockcopolymers.

There are many ways to apply the polymer solution to become theadditional layer on the polymer-grafted first layer surface of a metalarticle. Procedures commonly known in coating applications can be usedas long as they provide for good wetting of the first layer surface bythe polymer solution. Preferably the application procedure will allowfor the control of the parameters of the polymer layer such as layercomposition, thickness, and integrity. Thus, the polymer solution can beapplied on the first layer surface by dipping the surface to be coatedin the polymer solution, by spraying the polymer solution on the firstlayer surface, by pouring or spreading the solution onto the first layersurface, or any other technique known to those skilled in the art. Afterthe solution is applied to the first layer surface, excess solvent isevaporated. Various means to control the amount of solution remaining onthe first layer surface before and during evaporation of the solvent canbe used to control the thickness and homogeneity of the additionallayer. These procedures include spreading the solution and stripping itsexcess by a centrifugal force, spreading and removing the excesssolution by a spreading tool, dosed spraying, and those procedures thatare generally known in the art of polymer coating.

In a preferred embodiment of the invention, the compositions of thegrafted first layer and the additional layer are chosen such that atleast one polymer component of the additional layer is well compatiblewith the polymer of the first layer. Compatibility between the layersimproves the wetting of the first layer by the solution of theadditional layer and facilitates the formation of a contiguous andwell-adherent polymer matrix. Thus, the polymer film of the additionallayer may be designed so that it has the desired composition, thicknessand physical properties, such as morphology, phase structure, glasstransition, and crystallinity, while being capable of being applied in asimple coating technique.

According to another embodiment of the invention, the polymer solutionof the additional layer may contain one or more biologically activeagents that is/are released when a device with the polymer matrix isplaced in an appropriate aqueous environment. The biologically activeagent may be either dissolved in the solution containing the polymer, orit can be dispersed in the solution of the polymer in a form of solidparticles. In either case, the biologically active agent will becomeincorporated in the polymer film during the solidification of thepolymer layer by solvent evaporation.

The rate of the release of the biologically active agent can becontrolled through the composition and other parameters of the polymeradditional layer. The parameters such as layer thickness, morphology,phase structure, hydrophobicity, degree of hydration, the ratio ofcrystalline and amorphous phases, glass-transition temperature of thepolymer are relevant to release control. These parameters can becontrolled through the selection of polymers and their applicationprocedures.

Further, other blends can be used in additional or optional barrierlayers. While polyesters like polylactide (PLA) and polycaprolactone(PCL) are rather hydrophobic polymers, exhibiting a low degree ofhydration, poly(ethylene oxide) (PEO) is a hydrophilic polymer and issoluble in water. Thus a polymer film composed of polylactide and apolylactide/poly(ethylene oxide) block copolymer can form a two phasesystem with a hydrophobic phase, rich in PLA, and a hydrophilic phase,rich in PEO. The degree of hydration of the polymer and, consequently,the permeability of the polymer film for water and incorporatedhydrophilic biologically active agents can be increased by increasingthe fraction of the hydrophilic phase, such as PLA/PEO block copolymer,in the blend. Thus, through the variation of the PLA/PEO copolymer inthe film the release rate of certain biologically active agents can becontrolled. Similarly, depending on the degree to which a biologicallyactive agent is hydrophilic or hydrophobic, other combinations ofpolymers can be used to control the release rate of biologically activeagents.

In a polymer matrix with more than one additional layer, the outermostadditional sublayer may function as a skin, i.e., this layer either doesnot include the biologically active agent or its concentration in theskin layer is significantly lower than that in the underlying additionalsublayers. The skin layer can be used to further control the release ofthe biologically active agent. Additional skin layers may be applied toimprove the biocompatibility to the device.

The polymer layers may contain up to about 60% of the biologicallyactive agent by weight, depending on the physical properties of thebiologically active agent, such as its solubility in water, itscrystalline forms and compatibility with the polymer matrix forming thelayer. It is anticipated that a content of biologically active agentclose to the upper limit of this range can be more easily achieved withlow-solubility compounds, which at the same time exhibit a highadherence to the polymer of the additional layer. On the other hand,biologically active agents with high solubility or pure miscibility withthe polymer matrix will need to be in the lower portion of this range. Atypical range of the biologically active agent content for mostapplicable compounds will be between 1 to 50% by weight. The overallweight of the coating (polymer matrix plus biologically active agent) onthe device is typically very important. Within the constraits ofadequate clinical efficacy, the total dose of polymer plus a drug shouldbe minimized to avoid long term side effects, including delayedendothelialization of the arterial wall, prolonged inflammation causedby the presence of the polymers and the degrading oligomers and finalmetabolites.

The weight of the coating attributable to the biologically active agentcan be in the range of about 0.1 microgram to about 500 micrograms ofbiologically active agent per cm² of the gross surface area of thedevice. More preferably, the weight of an active drug or a biologicallyactive agent in the coating is between about 1 microgram and about 100micrograms per cm² of the nominal surface area of the device. Thisquantity of biologically active agent is generally required to provideadequate activity under physiological conditions.

The coating (polymer matrix plus biologically active agent) thickness ofa presently preferred composition will typically be in the range ofabout 0.01 micrometers to about 100 micrometers. This level of coatingthickness is generally required to provide an adequate density ofbiologically active agent to provide adequate activity underphysiological conditions and minimize the unwanted reactions from thesurrounding tissue to the degrading polymer. A more preferred thicknessof coating is between 0.01 μm to about 10 μm.

In one example employing the principles of the present invention, ametal stent is grafted with a bioabsorbable polylactide. It should beunderstood, however, that the present example may be applied to othersurfaces such as glass or ceramic surfaces. The metal surface isactivated with silane derivatives, as shown in FIGS. 1-3.

In a particular example, stainless steel stents (316 L) or cobaltchromium (L605) stents were placed in commercially available ENPREPsolution (45 g in 750 ml of water) and incubated at 70-100 C for 1 hour.The stents were rinsed in water twice and isopropanol (IPA) twicerespectively. Two silane agents that may be employed for this inventioncan be obtained commercially from Dow Corning with the following catalognumbers: Z6911 for sulfhydryl functional group; and Z-6040 for thesilane agent with epoxy functional group. The surface activated stentswere then incubated in an IPA and water solution of mixed silanederivatives containing both sulfhydryl group(3-mercaptopropyltrimethoxy-silane) and epoxy groups(Glycidoxypropyltrimethoxysilane, Z-6040 from Dow Corning), for 1 hourunder agitation. The silane treated stents are then rinsed with IPA,water and air dried for surface inspection. The silanized surface isfurther cured in oven at 60-100 C for about 1 hour.

After activation of the surface, the sulfhydryl group was coverted tosulfonic acid, and the epoxy group to a hydroxyl and an amine group, asshown in FIGS. 4-5. The sulfhydryl terminals on the surface can beconverted into sulfonic acid by using H₂O₂ in an aqueous medium (10 mlmethanol/20 ml of 30% H₂O₂ solution). The solution is stirred at roomtemperature for 24 hours. (In the particular example described above,the stents were then washed by copious amounts of de-ionized water.) Theconversion of the epoxy group into a dual or multiple functionalterminals for subsequent ring opening polymerization is achieved byreacting the epoxy carrying silanized surface with a suitable diol, suchas 1,3-propanediol, or a diamine, such as lysine ethylester, in anorganic solution. A typical example of the conversion involves a lysineethylester under reflex conditions in tetrahydrofuran (THF) for 2-4hours. (In the particular example described above, the stents are thenwashed with THF and dried in vacuum over night to produce a surface withboth sulfonic acid, hydroxyl and amine terminals.) Thereafter,ring-opening polymerization, as shown in FIG. 6, is initiated.

The functionalized stents are then transferred into a glass reactorcontaining d,l-lactide monomer (for instance, the lactone dimer fromPurac USA). The reactor is then degassed and heated to about 120-150 Covernight to complete the graft polymerization on the surface. Thereactor is then open and the content washed with THF and dried in vacuumoven before subsequent coating processes. The amount of the graftedpoly(d,l-lactide) layer on the stent surfaces can be determined by theweight gain before and after the ring opening polymerization and byanalyzing the surface composition using techniques such as time offlight secondary ion mass spectroscopy (TOF-SIMS) and ESCA (ElectronSpectroscopy for Chemical Analysis).

Although the present invention has been described above with respect toparticular preferred embodiments, it will be apparent to those skilledin the art that numerous modifications and variations can be made tothese designs without departing from the spirit or essential attributesof the present invention. Accordingly, reference should be made to theappended claims, rather than to the foregoing specification, asindicating the scope of the invention. The descriptions provided are forillustrative purposes and are not intended to limit the invention norare they intended in any way to restrict the scope, field of use orconstitute any manifest words of exclusion.

1. A composition comprising crosslinked silane derivatives linked to asurface having at least two functional terminals comprising an epoxidegroup and a sulfhydryl group, wherein the sulfhydryl group is oxidizedto form sulfonic acid which serves as an in situ catalyst for ringopening polymerization, in suitable solvent or in bulk, to graft a firstlactone polymer layer, and a second polymer layer is at least one ofdeposited, coated or sprayed on top of the first polymer layer, saidsecond polymer layer having a therapeutic agent contained therein, thetotal thickness of the composition being in the range of about 0.01 toabout 100 micrometers and wherein the weight of the therapeutic agent isin the range from about 0.1 to about 500 micrograms per squarecentimeter of surface area.
 2. The composition of claim 1 wherein thetherapeutic agent comprises an anti-proliferative agent.
 3. Thecomposition of claim 1 wherein the therapeutic agent comprises ananti-inflammatory agent.
 4. The composition of claim 1 wherein thetherapeutic agent comprises an anti-thrombotic drug.